The compounds of the invention are known for their coronary dilating and antihypertensive activity from U.S. Pat. No. 4,705,797. However, the anhydrous form of such compounds is novel and forms part of the present invention.
A particularly preferred compound is methyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate (lercanidipine), and pharmaceutically acceptable salts thereof. These compounds can be prepared according to the methods cited in U.S. Pat. No. 4,705,797 or the methods disclosed herein.
Also, particularly preferred are the resolved enantiomers of lercanidipine. The preparation of the individual enantiomers is described in the present specification.
Arteriosclerosis, a generic term for thickening and hardening of the arterial wall, is responsible for many deaths in the United States and other westernized societies. One type of arteriosclerosis is atherosclerosis, a disorder of the larger arteries that underlies most coronary artery disease, aortic aneurysm, and arterial disease of the lower extremities. Atherosclerosis plays a major role in cerebrovascular disease and is a leading cause of death in the United States, both above and below age 65 (E. L. Bierman in Harrison's Principles of Internal Medicine XII Ed., page 992 (1991)).
It is now recognized that atherosclerosis is a multifactorial process that, when leading to clinical sequelae, is based on extensive proliferation of migrated smooth muscle cells (myocytes) within the intima of the affected artery. The atherosclerotic plaque formation is believed to be the result of three fundamental biological processes. These are:
1) migration and proliferation of intimal smooth muscle cells, together with variable numbers of accumulated macrophages and T-lymphocytes; PA1 2) formation by the proliferated smooth muscle cells of large amounts of connective tissue matrix, including collagen, elastic fibers, and proteoglycans; and PA1 3) accumulation of lipid, principally in the form of cholesterol esters and free cholesterol within the cells as well as in the surrounding connective tissues. PA1 Ar is: 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or 5 benzofurazan-4-yl, PA1 A is a branched chain alkylene radical having from 2 to 6 carbon atoms, PA1 R is a straight or branched chain alkyl radical having from 1 to 6 carbon atoms, optionally mono-substituted by an alkoxy substituent having from 1 to 6 carbon atoms, PA1 R.sub.1 is hydrogen, hydroxy, or an alkyl radical having from 1 to 4 carbon atoms, and PA1 R.sub.2 is hydrogen, or methyl.
(R. Ross et al., Science, 180: 1332 (1973); R. Ross et al., N. Eng. J. Med., 295: 369 (1976); R. W. Wissler et al., Prog. Cardiovasc. Dis., 18: 341 (1976)).
In addition, a number of experimental reports ascribe a key role to the oxidative modification of low density lipoproteins (LDL) in the early stages of atherosclerosis in humans, where hypercholesterolemia represents the major risk factor associated with the increased incidence of the disease. Available data has lead to the belief that LDL can undergo oxidative modification (D. Steinberg et al., N. Eng. J. Med., 320: 915 (1989); J. L. Witztum, Lancet, 344: 793 (1994)) and that oxidized LDL has been shown to promote atherogenesis by a number of mechanisms, including enhanced uptake of LDL in tissue macrophages which leads to lipid accumulation and chemotactic activity for monocytes (M. S. Brown et al., Ann. Rev. Biochem., 52: 223 (1983)), and cytotoxicity to arterial wall endothelial cells (S. Parthasarathy et al., Prog. Lipid Res., 31: 127 (1992)).